GENEVA (Genes and Environment in Veterans with ALS) Reports that ALS risk was greater among veterans deployed to the 1990-1991 Persian Gulf War prompted the Department of Veterans Affairs (VA) to establish a National Registry of Veterans with ALS. The registry, established in 2004, enrolled 1,573 US veterans with neurologist-confirmed ALS. Information in the VA Registry includes ALS diagnosis and other clinical details and mortality ascertained through July 31, 2013. GENEVA is a case-control study of 631 ALS cases from the VA registry and 975 matched veteran controls. Information is available on demographics, lifetime occupational history, hobbies, home pesticide use, use of tobacco, caffeine, and alcohol, residential history, physical trauma, and family history of ALS of other neurodegenerative diseases. Our initial studies in GENEVA focused on military service, deployment, and exposures. We found that ALS risk was similar among veterans of the Air Force, Army, Marines, and Navy. Risk was lower among officers and higher among veterans whose longest deployment was World War II or the Korean War. ALS was positively associated with exposure to herbicides for military purposes, nasopharyngeal radium, exhaust from heaters or generators, high-intensity radar waves, explosions within one mile, herbicides in the field, mixing and application of burning agents, burning agents in the field, and Agent Orange in the field, with odds ratios between 1.50 and 7.75. These results provide clues to potential causal factors underlying the apparent increase of ALS in veteran populations. We also evaluated associations between military factors and ALS survival. We observed 446 deaths (median follow-up 28 months, 24,267 person-months). Survival was shorter among cases who served before 1950, who were deployed to World War II, or who mixed and applied burning agents. In contrast, survival was longer among cases exposed to paint, solvents, or petrochemical substances, to local food, or to burning agents or Agent Orange in the field. Most military-related factors were not associated with ALS survival. Suggestions that ALS survival may be shortened by certain exposures are potentially important given the large number of U.S. military veterans, but they are novel and require confirmation. ALS may be associated with low body mass index (BMI) at the time of diagnosis. However, the role of premorbid BMI and weight change in the development of ALS and survival after diagnosis is not clear. We evaluated the association of BMI and BMI change at different ages with ALS risk using GENEVA data. Compared to a moderate increase in BMI between age 25 and 40, stable or decreasing BMI was associated with a 60% increase in ALS risk. Greater BMI at age 40 but not age 25 decreased ALS risk. Associations were similar between bulbar and spinal ALS but stronger for those with <1 year between symptom onset and diagnosis. We found no association between pre-diagnostic BMI or BMI change and survival. A decreasing BMI from early to middle age and a low BMI in middle age may be positively associated with ALS risk. In an add-on study, Veterans with ALS and Lead Exposure (VALE), we evaluated the relationship of blood metals to ALS using 163 ALS cases from the VA Registry and 229 controls from GENEVA. We measured metals with inductively coupled plasma mass spectrometry and evaluated bone turnover using biomarkers of bone formation (PINP) and resorption (CTX). Blood lead levels were higher among cases than controls. CTX was also greater in cases than controls, but PINP was the same. Each doubling of blood lead was associated with a 2.6-fold increase in ALS risk regardless of adjustment for bone turnover. These results corroborate our earlier finding that elevated blood lead is associated with increased ALS risk and suggest that increased bone turnover in ALS cases does not fully explain this association. We also evaluated whether blood lead and bone turnover were associated with higher risk of death after ALS diagnosis. A doubling of lead was associated with a 1.4-fold risk of death. A doubling of plasma CTX was associated with a 2.0-fold risk of death, whereas a doubling of plasma PINP was associated with a 0.59-fold risk of death. Higher blood lead level and greater bone turnover may be related to shorter ALS survival. We examined associations of ALS with blood levels of selenium (Se), zinc (Zn), copper (Cu), and manganese (Mn). Both Se and Zn reduced risk of ALS by 60%; the associations were stronger among patients with worse function. Cu was associated with a 3.4-fold increase in ALS risk, but there was no clear cut relationship of ALS with Mn. Adjustment for lead levels attenuated the positive association of ALS with Cu but did not change associations with Se, Zn, or Mn. Thus deficiencies of Se and Zn and excess Cu may have a role in ALS etiology. Presently we are evaluating the role of these four trace metals in ALS survival. A complete occupational history was collected from GENEVA participants. Susan Woskie, an industrial hygienist, and a team of specialists used these histories to assign exposures to several agents of interest, all of which have been implicated in ALS by one or more studies but none conclusively. These exposures include lead, mercury, selenium, arsenic, PCBs, hydrocarbon solvents, chlorinated solvents, formaldehyde, EMF, and viral agents. We plan to use this information for studies of ALS risk and survival. Swedish National Registers I collaborate with Fang Fang and Weimin Ye at the Karolinska Institute on studies based on the Swedish National Registers. ALS and diabetes: We studied the association of diabetes with ALS in 5,108 ALS cases and 25,540 individually matched population controls during 1991-2010. Information on ALS and pre-existing diabetes was retrieved from the nationwide Swedish Patient Register. Diabetes was associated with a 21% decrease in ALS risk. The inverse association was stronger for non-insulin-dependent diabetes (34% decrease) than for insulin-dependent diabetes (17% decrease) and was noted only among individuals age 70 or older. For younger individuals (<50 years), preexisting insulin-dependent diabetes was associated with a 5.4-fold higher risk of ALS. Our study provides important evidence for an association between premorbid diabetes and ALS, highlighting also the importance of taking into account age, insulin dependence and diabetes duration when examining such an association. Information on occupation from the Swedish census was evaluated with a job exposure matrix to assign exposures. We are using this information to study workplace exposures and ALS risk. Occupational Cohorts Certain occupations and occupational exposures may be related to ALS, but data are sparse and inconsistent. Our results from the New England ALS study identified several associations with ALS. To extend this work, we collaborated with Lynne Pinkerton at NIOSH on a study of flight attendants. Concern exists about potential neurological effects among flight crew of exposure to contaminants from engine oil in aircraft cabin air. We evaluated mortality from neurodegenerative diseases among 11,311 former US flight attendants. We ascertained vital status through 2007 and conducted life table analyses to obtain standardized mortality ratios. ALS mortality was elevated two-fold compared to the US population, based on 9 deaths. There was no clear pattern in risk related to exposure duration. Mortality from other neurodegenerative diseases was not elevated. Our findings are limited due to small numbers of observed deaths, but suggest that flight attendants may have an increased risk of ALS, possibly related to exposure to tricresyl phosphates in engine oil.